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7.2 Cardiac Stem Cells (CSCs)
Beltrami et al gave the first report of these endogenous regenerating myocardial
stem cells in rats in 2003 [ 1 ]. This group showed the existence of Lin− c-kit+ (Lin−:
negative for various cell specific lineage markers and ckit+: positive for ckit, a trans-
membrane receptor for stem cell factor) cells located in the adult rat myocardium
that were positive for Ki67, a mitotic marker and GATA4 and Nkx2.5, transcription
factors associated with early cardiac development. In vitro, these cells demonstrated
self-renewal capability and also the capacity to differentiate into myocardial, endo-
thelial, and smooth muscle cell lineages. Most strikingly, transplantation of these
cells into the hearts of syngeneic rats post myocardial infarction (MI) reduced the
extent of myocardial damage compared with controls, and the transplanted cells
were able to give rise to myocyte, endothelial, and smooth muscle cell lineages in
vivo. Thus, these cells were shown to have all the characteristic features of putative
cardiac stem cells. After initial report of rat CSCs, c-kit-positive CSCs have been
identified in mice [ 2 ], dogs [ 3 ] and now also in human beings [ 4 ]. All these reports
have unequivocally documented that c-kit+ CSCs are self-renewing, clonogenic and
multipotent both in vitro and in vivo. The c-kit+ CSCs are distributed throughout the
left and right ventricle but tend to concentrate in the atria and apex, since these ana-
tomical areas are exposed to low levels of hemodynamic stress. For details about the
niche of CSCs, the readers may refer to Leri et al. [ 5 ]. Regarding the origin of these
cells, some studies have reported that c-kit+ CSCs originate from the developing
heart [ 6 ]. On the other hand, contrastingly, several studies have suggested that c-kit+
cardiac cells are mobilized from the bone marrow (BM) and recruited to the heart
following injury, and hence may have an extra-cardiac origin [ 7 ].
In addition to c-kit, other specific phenotypic markers define other “types” of
CSCs in the myocardium, although some of these markers may be co-expressed by
some other cells. Various reported populations of CSCs include (1) side population
cells that are known to express abcg2, an ABC transporter that effluxes dyes, similar
to mdr1; (2) CSCs expressing stem cell associated-marker stem cell antigen-1 or
Sca-1+; CSCs expressing (3) CSCs expressing transcription factor Islet1 or Isl1+;
CSCs expressing and (4) CSCs derived from cardiospheres or CDCs migrate out of
cardiac explants and grow as 3D multicellular clusters [ 8 ] (Table 7.1). On the basis
of their differentiation property, immature cardiac cells have been classified into
four classes: CSCs, progenitors, precursors, and amplifying cells. The first three cell
types express c-kit, mdr1/abcg2, and Sca-1, whereas the last type no longer expresses
these antigens [ 19 ]. It has been reported that Notch1 regulates the transition of
CSCs from the primitive immature phenotype to that of amplifying myocytes.
Activation of the Notch1 pathway up regulates the expression of Nkx2.5 that drives
the differentiation of CSCs to the myocyte lineage. Activation of Notch 1 is also
known to enhance the proliferative phase of cardiomyocytes, favor their survival
and extend their lifespan both in vitro and in vivo [ 5 ]. An alternative source of CSCs
has been identified in the epicardium. Epicardium-derived progenitor cells (EPDCs)
express Wt1, an embryonic epicardiac gene and exhibit characteristics of CSCs
S. Kaur et al.